Chemoresistance hinders the curative cancer chemotherapy. To define the role of the DNA methylation-regulated microRNA (miR) genes in the chemoresistance of bladder cancer, we performed both DNA methylomic and miRomic analyses of a multi-chemosensitive (5637) versus a multi-chemoresistant (H-bc) cell line and found that miR-193a-3p is hypermethylated/silenced in 5637 and hypomethylated/expressed in H-bc cells. A forced reversal of its level turned around the chemoresistance in the cultured cells and the tumor xenografts in nude mice. Three of its targets: SRSF2, PLAU and HIC2, work in concert to relay the miR-193a-3p's impact on the bladder cancer chemoresistance by modulating the activities of the following five signaling pathways: DNA damage, Notch, NF-κB, Myc/Max, and Oxidative Stress. In addition to the mechanistic insights in how the newly identified miR-193a-3p/SRSF2,PLAU,HIC2/five signaling pathway axis regulates the chemoresistance of bladder cancer cells, our study provides a new set of diagnostic targets for the guided personalized chemotherapy of bladder cancer.

MicroRNAs have been identified as key players in the development and progression of osteosarcoma, which is the most common primary malignancy of bone. Sequencing-based miR-omic and quantitative real-time PCR analyses suggested that the expression of miR-193a-3p and miR-193a-5p was decreased by DNA methylation at their promoter region in a highly metastatic osteosarcoma cell line (MG63.2) relative to their expression in the less metastatic MG63 cell line. Further wound-healing and invasion assays demonstrated that both miR-193a-3p and miR-193a-5p suppressed osteosarcoma cell migration and invasion. Moreover, introducing miR-193a-3p and miR-193a-5p mimics into MG63.2 cells or antagomiRs into MG63 cells confirmed their critical roles in osteosarcoma metastasis. Additionally, bioinformatics prediction along with biochemical assay results clearly suggested that the secretory small GTPase Rab27B and serine racemase (SRR) were direct targets of miR-193a-3p and miR-193a-5p, respectively. These two targets are indeed involved in the miR-193a-3p- and miR-193a-5p-induced suppression of osteosarcoma cell migration and invasion. MiR-193a-3p and miR-193a-5p play important roles in osteosarcoma metastasis through down-regulation of the Rab27B and SRR genes and therefore may serve as useful biomarkers for the diagnosis of osteosarcoma and as potential candidates for the treatment of metastatic osteosarcoma.

Chemoresistance prevents the curative cancer therapy, our understanding of which remains inadequate. Among the differentially expressed genes between the chemosensitive (5637) and chemoresistant (H-bc) bladder cancer cell lines, the expression level of the PSEN1 gene (presenilin 1), a key component of the γ-secretase, is negatively correlated with chemoresistance. A small interfering RNA mediated repression of the PSEN1 gene suppresses cell apoptosis and de-sensitizes 5637 cells, while overexpression of the presenilin 1 sensitizes H-bc cells to the drug-triggered cell death. As a direct target of microRNA-193a-3p that promotes the multi-chemoresistance of the bladder cancer cell, PSEN1 acts as an important executor for the microRNA-193a-3p's positive impact on the multi-chemoresistance of bladder cancer, probably via its activating effect on DNA damage response pathway. In addition to the mechanistic insights, the key players in this microRNA-193a-3p/PSEN1 axis are likely the diagnostic and/or therapeutic targets for an effective chemotherapy of bladder cancer.

BackgroundChemoresistance is a major obstacle to the curative cancer chemotherapy and presents one of the most formidable challenges in both research and management of cancer.ResultsFrom the detailed studies of a multi-chemosensitive (5637) versus a chemoresistant (H-bc) bladder cancer cell lines, we showed that miR-193a-3p [GenBank: NR_029710.1] promotes the multi-chemoresistance of bladder cancer cells. We further demonstrated that lysyl oxidase-like 4 (LOXL4) gene [GenBank: NM_032211.6] is a direct target of miR-193a-3p and executes the former’s impact on bladder cancer chemoresistance. The Oxidative Stress pathway activity is drastically affected by a forced reversal of miR-193a-3p or LOXL4 levels in cell and may act at the downstream of LOXL4 gene to relay the miR-193a-3p’s impact on the multi-chemoresistance in both cultured cells and the tumor xenografts in nude mice.ConclusionsIn addition to a new mechanistic insight, our results provide a set of the essential genes in this newly identified miR-193a-3p/LOXL4/Oxidative Stress axis as the diagnostic targets for a guided anti-bladder cancer chemotherapy.Electronic supplementary materialThe online version of this article (doi:10.1186/1476-4598-13-234) contains supplementary material, which is available to authorized users.

An association has been reported between miR-34a-5p and several types of cancer. Specifically, in this study, using systematic observations of multi-drug sensitive (G-292 and MG63.2) and resistant (SJSA-1 and MNNG/HOS) osteosarcoma (OS) cell lines, we showed that miR-34a-5p promotes the multi-drug resistance of OS through the receptor tyrosine kinase CD117, a direct target of miR-34a-5p. Consistently, the siRNA-mediated repression of CD117 in G-292 and MG63.2 cells led to a similar phenotype that exhibited all of the miR-34a-5p mimic-triggered changes. In addition, the activity of the MEF2 signaling pathway was drastically altered by the forced changes in the miR-34a-5p or CD117 level in OS cells. Furthermore, si-CD117 suppressed the enhanced colony and sphere formation, which is in agreement with the characteristics of a cancer stem marker. Taken together, our data established CD117 as a direct target of miR-34-5p and demonstrated that this regulation interferes with several CD117-mediated effects on OS cells. In addition to providing new mechanistic insights, our results will provide an approach for diagnosing and chemotherapeutically treating OS.